DESCRIPTION (Taken directly from the application) The syndrome of resistance to thyroid hormone is characterized by elevated thyroid hormone levels and inappropriate TSH secretion due in almost all cases to point mutations in the TR-b locus. Studies of these naturally occurring TR mutations in vitro have yielded useful insights into the syndrome of RTH. Unfortunately, the generalizability of these studies to the patient's disorder is not always clear and because of their artificial nature may not always be secure. Confounding these issues is the clinical heterogeneity of RTH in families with the same mutation and the description of at least distinct varieties of RTH in man: generalized RTH (GRTH) and central RTH (CRTH). The goal of these studies will be to define the clinical differences between these forms of RTH and provide a molecular explanation for these differences. This proposal will allow the Principal Investigator to devote additional time to the clinical study of patients with RTH and the mentoring of new investigators entering the field of thyroid research. The candidate has recently accepted the position of Chief of Endocrinology and Professor of Medicine at the University of Chicago. He has independent support to study thyroid hormone action (R01 DK49126 and R01 DK53036) in animals and man and TRH signaling pathways in the pituitary (R01 DK50564). He directs a CRC protocol to evaluate and categorize patients with RTH. He actively mentors three BC endocrinologists in thyroid research, each having NIH K08 support for their projects. With his previous research and mentoring success, in an environment rich with academic opportunities, this award will allow him to increase his mentoring activities and to enhance his own commitment to patient-oriented research.